In the 1970s, Guidotti demonstrated that the trans-synaptic induction of tyrosine-hydroxylase depends on the nuclear translocation of protein-kinaseA catalytic subunits and the phosphorylation of specific nuclear proteins (1).

Together with Costa (1975), he reported that benzodiazepines, allosterically acting at specific GABAA receptor sites, enhance GABA’s gating of Cl- channels (3,4). Pursuing this research trend, he discovered imidazenil, an imidazo-benzodiazepine acting as a selective positive allosteric modulator at GABAA receptors. Unlike other benzodiazepines, imidazenil is devoid of tolerance or dependence liabilities and may become the drug of choice to treat psychoses associated with GABAergic dysfunction (4-6). He also discovered (1990s) that SSRIs preferentially facilitate GABA's action at GABAA receptors by increasing brain neurosteroid content with potency greater than 5HT-reuptake inhibition (7).

Guidotti and his co-investigators (1998-2000) pioneered studies on the role of reelin in human cortex. Reelin is synthesized and secreted from GABAergic neurons into the extracellular matrix. He demonstrated that reelin acting at integrin receptors facilitates the translation of mRNAs located in dendrites of cortical pyramidal neurons (8). In cortical GABAergic neurons of schizophrenia patients, reelin and GAD67 expressions are downregulated (8), very likely by epigenetic promoter hypermethylation (9-12) related to high-order chromatin remodeling dysfunctions. Guidotti and collaborators recently discovered that valproate, an effective coadjuvant in psychosis treatment, inhibits brain chromatin histone deacetylases and promotes histone tail acetylation thereby downregulating methylation of promoters expressed by cortical GABAergic neurons (11). He proposes that demethylation of promoters expressed in GABAergic neurons could be a mechanism operative in the antipsychotic action of valproate (11,12).